IL-13 is a Th2 cytokine that has been shown to be critical for the development of allergic inflammation. IL-13 mediates its effects via a complex receptor system that includes IL-4Ralpha and two other cell surface proteins, IL-13Ralpha1 and IL-13Ralpha2. IL-13Ralpha1 binds IL-13 with low affinity by itself, but when paired with IL-14Ralpha, it binds IL-13 with high affinity and forms a functional IL-13 receptor that signals. Expression of IL-13Ralpha2 in vitro was insufficient to render cells responsive to IL-13, despite high affinity binding even in the presence of IL-4Ralpha. IL-13Ralpha2 has a short cytoplasmic tail, which contains no box 1 or box 2 signaling motifs, supporting that it has no signaling function. The inability of IL-13Ralpha2 expression to confer IL-13 responsiveness despite high affinity binding, along with the finding of soluble IL-13Ralpha2 in vivo, has led to speculation that IL-13Ralpha2 is a decoy receptor. This theory was further supported by the recent characterization of the IL-13Ralpha2-deficient mice that were found to have elevated IgE levels. Although IL-13Ralpha indeed may act as a decoy receptor under some circumstances, it may have other yet unrecognized functions. Recently, we have observed that allergen-induced airway hyperreactivity (AHR) is enhanced in mice that overexpress IL-13Ralpha2 in the lungs. Furthermore, our collaborator, Marsha Wills-Karp, has observed that allergen-induced AHR is decreased in mice that are deficient in IL-13Ralpha2 when compared with wild-type mice. In contrast to the allergen sensitization and challenge model, we observed no change in AHR in mice that overexpress IL-13Ralpha2 in the lungs following IL-13 treatment intratracheally for 3 days. These observations support that under some circumstances IL-13Ralpha2 may contribute to IL-13 responses and that the contribution of IL-13Ralpha2 may be distinct under conditions of chronic vs. acute inflammation. The studies proposed herein will examine this possibility by testing the 2 following hypotheses: (1) IL-13Ralpha2 is not a simple decoy receptor, but can contribute to the allergic response during chronic inflammation; and (2) the subcellular localization of IL-13Ralpha2, as well as the level and timing of IL-13Ralpha2 expression, may be critical in determining its final contribution to the IL-13 response. In Aim #1, we will determine the effect of IL-13Ralpha2 overexpression in 3 different models of chronic allergic inflammation. In Aims #2-3, we will elucidate the mechanism by which IL-13Ralpha2 influences IL-13 responses. We will examine how the level, subcellular location, and cell type of IL-13Ralpha2 expression relates to its function. By providing information about how responses to IL-13 are regulated at the receptor level, our results will complement proposals in this program project that study regulation of IL-13 production and evaluate genes important for asthma that are activated by both IL-4 and IL-13 or by IL-13 alone.